I. Field of the Invention
The present invention provides novel organic compounds, useful for antifertility purposes. Particularly, the present invention provides a novel polypeptide isolated from the mammalian pineal gland. More particularly, there is provided a novel bovine pineal tripeptide and salts thereof with antigonadotrophic activity.
Also provided by the present invention are novel methods for isolation of a bovine pineal tripeptide from the bovine pineal gland.
Gonadotropins are a class of substances which stimulate male and female gonads, thus ordinarily representing profertility or fertility-maintaining agents. The gonadotropins include luteinizing hormone (LH) which stimulates ovulation and post-ovulatory progesterone production in the female ovaries. Another gonadotropin, follicle stimulating hormone (FSH), is a secondary pituitary hormone which stimulates the pre-ovulatory maturation of the Graafian follicles of the ovary, thus encouraging estrogen production therein. Thus, both LH and FSH stimulate estrogen or progesterone production and release from the ovaries, and are thereby essential for the establishment and maintenance of fertility.
In the male, FSH supports the germinal cells of the testes, while LH stimulates testosterone production. Hence these gonadotropins are essential to spermatogenesis and thus fertility in the male.
In addition to LH and FSH an hormonal substance from the hypothalamus, gonadotropin releasing hormone (GnRH), is known to be an endogenous agent for the stimulation of LH and FSH release. This substance is alternately known as LH-RH (luteinizing hormone releasing hormone) or LRF (luteinizing hormone releasing factor).
Because the gonadotropins are essential to the maintenance of fertility in both the male and the female, antigonadotrophic substances have been sought for use as antifertility or fertility-suppressing agents.
One fruitful source of antigonadotrophic substances has been the mammalian pineal gland, from which two broad classes of antigonadotrophic compounds have been isolated: polypeptides and indoles. With regard to the latter class, the most widely examined antigonadotrophic substance is melatonin, which, inter alia, reduces the effects of MSH (melanocyte stimulating hormone). Other pineal-derived antigonadotrophic indoles include serotonin, 5-hydroxytryptophol, 5-methoxytroptophol, and N-acetylserotonin.
With regard to pineal antigonadotrophic polypeptides, one important such substance is arginine vasotocin, which was first isolated by Milcu, S.M., et al., Endocrinology 72:563-566 (1963). For the structure of arginine vasotocin, see Cheesman, Biochim. Biophys. Acta. 207:247-253 (1970) and German offenlegungsschrift 2,739,492, published Mar. 3, 1978 (Derwent Farmdoc CPI No. 18163A).
Various other pineal antigonadotrophic polypepetides have been reported by various workers. For a brief review of reports of such polypepetides, see Table 3 (pages 164-166 of Reiter, Russell J., et al., "Pineal Antigonadotrophic Substances: Polypeptides and Indoles", Life Sciences 21:159-172 (1977).
A further review of pineal antigonadotrophic polypeptides, particularly a disclosure of certain uncharacterized (e.g., no amino acid content or amino acid sequence) polypepetides is provided by Orts, R.J., et al., "Antifertility Properties of Bovine Pineal Extracts: Reduction of Ovulation and Pre-Ovulatory Luteinizing Hormone in the Rat", Acta. Endocrinologica. 85:255-234 (1977), and Orts, R.G., "Reduction of Serum LH and Testosterone in Male Rats by a Partially Purified Bovine Pineal Extract", Biology of Reproduction 16:249-254 (1977).
II. Prior Art
The existence of pineal antigonadotrophic polypeptides and their antifertility properties is known in the art. See Orts, R.J., et al., "Antifertility Properties of Bovine Pineal Extracts: Reduction of Ovulation and Pre-Ovulatory Luteinizing Hormone in the Rat", Acta Endrocrinologica. 85:225-234 (1977), and Orts, R.J., "Reduction of Serum LH and Testosterone in Male Rats by a Partially Purified Bovine Pineal Extract", Biology of Reproduction 16:249-254 (1977). Moreover, a general review of both polypeptide-type and indole-type pineal anti-genadotrophic substances is provided by Reiter, Russell J., et al., "Pineal Antigonadotrophic Substances: Polypeptides and Indoles", Life Sciences 21:159-172 (1977), cited above.